In the elderly, dramatic age-related changes in brain and immune function occur that may compromise the effective communication between these two systems. Clearly, responses of the nervous system to stressors have modulatory effects on the immune system, and immune activation alters nervous system activity. Understanding the mechanisms involved in this bi-directional communication is critical for developing optimal treatment strategies for disease, and for maintaining health. In spite of its importance, information is limited as to how age-related changes in brain function affect its ability to modulate the immune system, or how aging changes in immune response affect immune to brain signaling. Therefore, the overall goal of this proposal is to investigate age-associated changes in sympathetic-immune interactions using rodents as a model for normal brain and immune system aging in humans. The two rat strains selected for study, Fischer 344 (F344) and Brown-Norway (BN), are strikingly different with respect to aging effects on sympathetic nerves in secondary lymphoid organs and immune responsiveness, possibly representing variability in aging of the elderly population. Aging differences in these two rat strains may confer differential susceptibility to diseases that increase in frequency with age. The rationale for studies in this proposal is summarized briefly here. (1) Sympathetic innervation of lymphoid organs is essential for normal immune function. (2) A consistent finding in both animals and humans is an age-related increase in sympathetic drive that is largely centrally mediated. (3) Immune function is compromised in aging, particularly cell-mediated immunity. (4) Altered sympathetic neurotransmission in secondary lymphoid organs affects immune reactivity in rats in a strain-specific manner. Specific Aim 1 investigates age-related changes in sympathetic drive, locally in secondary lymphoid organs. Specific Aim 2 studies immune signaling of central sympathetic pathways in response to antigenic challenge with a T-dependent protein antigen in aging. Specific Aim 3 explores possible mechanisms responsible for the age-related differences in sympathetic innervation of secondary lymphoid organs from these two rat strains.